Process for producing optically active β-amino aldehyde compound

ABSTRACT

The invention relates to a method of producing optically active β-aminoaldehyde compound (3) by reacting imine compound (1-1) or sulfone compound (1-2) with aldehyde compound (2) in the presence of an optically active pyrrolidine compound. 
                         
wherein each symbol is as defined in the specification.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is the U.S. national phase of International Patent Application No. PCT/JP2011/074073, filed on Oct. 19, 2011, which claims the benefit of Japanese Patent Application No. 2010-235793, filed Oct. 20, 2010, which are incorporated by reference in their entireties herein.

TECHNICAL FIELD

The present invention relates to a production method of an optically active β-aminoaldehyde compound.

BACKGROUND ART

An optically active β-aminoaldehyde compound is known to be useful for as an intermediate for producing, for example, a therapeutic drug for diabetes and a therapeutic drug for Alzheimer's disease.

Concerning a production method of an optically active β-aminoaldehyde compound, for example, non-patent document 1 discloses that β-amino-β-phenylpropanal can be obtained by reacting an aromatic imine compound with an aldehyde compound in the presence of (S)-proline. Non-patent document 1 also discloses that the objective optically active β-aminoaldehyde compound cannot be obtained by replacing the aromatic imine compound with an aliphatic imine in the above-mentioned method.

DOCUMENT LIST Non-Patent Document

-   Non-Patent Document 1: Angewandte Chemie International Edition, vol.     46, pages 609-611, 2007

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The aim of the present invention is to provide a new method capable of producing an optically active β-aminoaldehyde compound from an imine compound.

Means of Solving the Problems

Under the circumstances, the present inventors have studied a new production method of an optically active β-aminoaldehyde compound, and found that by a reaction in the presence of a particular asymmetric catalyst, an optically active β-aminoaldehyde compound can be produced from an imine compound, which resulted in the completion of the present invention. Accordingly, the present invention is as follows.

[1] A method of producing an optically active compound represented by the formula (3):

wherein R¹ is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from the following Group G1 or a hydrogen atom, R² is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from the following Group G1, a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from the following Group G1, a C₁-C₁₂ alkylthio group optionally having substituent(s) selected from the following Group G1, a protected amino group, a heterocyclic group optionally having substituent(s) selected from the following Group G2 or a hydrogen atom, R^(X) is an amino-protecting group, and the carbon atom marked with ** is an asymmetric carbon atom (hereinafter referred to as optically active β-aminoaldehyde compound (3)), which comprises a step of reacting a compound represented by the formula (1-1):

wherein R¹ and R^(X) are as defined above (hereinafter referred to as imine compound (1-1)), or a compound represented by the formula (1-2):

wherein

-   -   R¹ and R^(X) are as defined above, and         Ar^(X) is a phenyl group optionally having substituent(s)         selected from the following Group G2         (hereinafter referred to as sulfone compound (1-2)) with a         compound represented by the formula (2):         R²—CH₂CHO  (2)         wherein         R² is as defined above         (hereinafter referred to as aldehyde compound (2)), in the         presence of an optically active compound represented by the         formula (4):

wherein Ar¹ and Ar² are each independently a phenyl group optionally having substituent(s) selected from the following Group G2, a C₁-C₁₂ chain hydrocarbon group, a C₃-C₁₂ alicyclic hydrocarbon group or a hydrogen atom, R⁵ is a hydrogen atom, a fluorine atom, a hydroxyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ fluorinated alkyloxy group or a group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group or a C₆-C₂₀ aryl group, and the carbon atom marked with * is an asymmetric carbon atom (hereinafter referred to as optically active pyrrolidine compound (4)); <Group G1>: a group consisting of a C₆-C₂₀ aryl group optionally having substituent(s) selected from Group G2, an aromatic heterocyclic group optionally having substituent(s) selected from Group G2, a C₁-C₁₂ alkyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ alkyl group having C₈-C₂₀ aryl group(s) optionally having substituent(s) selected from Group G2, a C₁-C₁₂ alkoxy group having C₆-C₂₀ aryl group(s) optionally having substituent(s) selected from Group G2, a halogen atom, a C₂-C₁₃ alkylcarbonyl group, a C₂-C₁₃ alkoxycarbonyl group, a C₁-C₁₂ fluorinated alkyl group, a C₁-C₁₂ fluorinated alkyloxy group, a C₂-C₁₃ acyl group, a nitro group, a cyano group, a protected amino group and an oxo group <Group G2>: a group consisting of a C₁-C₁₂ alkyl group, a C₁-C₁₂ alkoxy group, a C₂-C₁₃ alkylcarbonyl group, a C₂-C₁₃ alkoxycarbonyl group, a C₁-C₁₂ fluorinated alkyl group, a C₁-C₁₂ fluorinated alkyloxy group, a C₂-C₁₃ acyl group, a nitro group, a cyano group, a protected amino group and a halogen atom [2] The method of the above-mentioned [1], wherein the reaction is carried out in a solvent. [3] The method of the above-mentioned [2], wherein the solvent is water. [4] The method of the above-mentioned [2], wherein the solvent is water containing an inorganic salt. [5] The method of the above-mentioned [4], wherein the inorganic salt is sodium chloride. [6] The method of the above-mentioned [2], wherein the solvent is an ether solvent. [7] The method of the above-mentioned [1], wherein R⁵ is a group represented by —OSiR⁶R⁷R⁸ wherein each symbol is as defined in the above-mentioned [1], and Ar¹ and Ar² are each independently a phenyl group having C₁-C₁₂ fluorinated alkyl group(s).

Effect of the Invention

The production method of the present invention can provide a new method capable of producing an optically active β-aminoaldehyde compound from an imine compound.

In addition, by using optically active pyrrolidine compound (4) having a particular structure, optically active β-aminoaldehyde compound (3) can be produced in good yield, superior enantioselectivity and diastereoselectivity (when R² in aldehyde compound (2) is not a hydrogen atom).

DESCRIPTION OF EMBODIMENTS

The present invention is explained in detail below.

In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

In the present specification, the “C₁-C₂₀ hydrocarbon group” means a C₁-C₂₀ aliphatic hydrocarbon group or a C₆-C₂₀ aromatic hydrocarbon group.

In the present specification, the “C₁-C₂₀ aliphatic hydrocarbon group” means a C₁-C₂₀ chain hydrocarbon group or a C₃-C₂₀ alicyclic hydrocarbon group.

In the present specification, the “C₁-C₁₂ aliphatic hydrocarbon group” means a C₁-C₁₂ chain hydrocarbon group or a C₃-C₁₂ alicyclic hydrocarbon group.

In the present specification, the “C₁-C₂₀ chain hydrocarbon group” means a C₁-C₂₀ alkyl group, a C₂-C₂₀ alkenyl group or a C₂-C₂₀ alkynyl group.

In the present specification, the “C₁-C₁₂ chain hydrocarbon group” means a C₁-C₁₂ alkyl group, a C₂-C₁₂ alkenyl group or a C₂-C₁₂ alkynyl group.

In the present specification, the “C₁-C₂₀ alkyl group” means a straight or branched chain alkyl group having 1 to 20 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, eicosyl and the like. Among them, a C₁-C₁₂ alkyl group is preferable, and a C₁-C₈ alkyl group is particularly preferable.

In the present specification, the “C₁-C₁₂ alkyl group” means a straight or branched chain alkyl group having 1 to 12 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. Among them, a C₁-C₈ alkyl group is preferable, and a C₁-C₄ alkyl group is particularly preferable.

In the present specification, the “C₁-C₈ alkyl group” means a straight or branched chain alkyl group having 1 to 8 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl and the like. Among them, a C₁-C₄ alkyl group is preferable.

In the present specification, the “C₁-C₆ alkyl group” means a straight or branched chain alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like. Among them, a C₁-C₄ alkyl group is preferable.

In the present specification, the “C₁-C₄ alkyl group” means a straight or branched chain alkyl group having 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like.

In the present specification, the “C₂-C₂₀ alkenyl group” means a straight or branched chain alkenyl group having 2 to 20 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl, 1-tridecenyl, 1-eicosenyl and the like. Among them, a C₂-C₁₂ alkenyl group is preferable, and a C₂-C₈ alkenyl group is particularly preferable.

In the present specification, the “C₂-C₁₂ alkenyl group” means a straight or branched chain alkenyl group having 2 to 12 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, 1-undecenyl, 1-dodecenyl and the like. Among them, a C₂-C₈ alkenyl group is preferable, and a C₂-C₄ alkenyl group is particularly preferable.

In the present specification, the “C₂-C₆ alkenyl group” means a straight or branched chain alkenyl group having 2 to 6 carbon atoms, and examples thereof include ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl and the like. Among them, a C₂-C₄ alkenyl group is particularly preferable.

In the present specification, the “C₂-C₂₀ alkynyl group” means a straight or branched chain alkynyl group having 2 to 20 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl, 1-tridecynyl, 1-eicosynyl and the like. Among them, a C₂-C₁₂ alkynyl group is preferable, and a C₂-C₈ alkynyl group is particularly preferable.

In the present specification, the “C₂-C₁₂ alkynyl group” means a straight or branched chain alkynyl group having 2 to 12 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-heptynyl, 1-octynyl, 1-nonynyl, 1-decynyl, 1-undecynyl, 1-dodecynyl and the like. Among them, a C₂-C₈ alkynyl group is preferable, and a C₂-C₄ alkynyl group is particularly preferable.

In the present specification, the “C₂-C₆ alkynyl group” means a straight or branched chain alkynyl group having 2 to 6 carbon atoms, and examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl and the like. Among them, a C₂-C₄ alkynyl group is preferable.

In the present specification, the “C₃-C₂₀ alicyclic hydrocarbon group” means a C₃-C₂₀ cycloalkyl group or a C₄-C₂₀ cycloalkenyl group.

In the present specification, the “C₃-C₁₂ alicyclic hydrocarbon group” means a C₃-C₁₂ cycloalkyl group or a C₄-C₁₂ cycloalkenyl group.

In the present specification, the “C₃-C₂₀ cycloalkyl group” means a cyclic alkyl group having 3 to 20 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cycloeicosyl and the like. Among them, a C₃-C₁₂ cycloalkyl group is preferable, and a C₃-C₈ cycloalkyl group is particularly preferable.

In the present specification, the “C₃-C₁₂ cycloalkyl group” means a cyclic alkyl group having 3 to 12 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like. Among them, a C₃-C₈ cycloalkyl group is preferable.

In the present specification, the “C₄-C₂₀ cycloalkenyl group” means a cyclic alkenyl group having 4 to 20 carbon atoms, and examples thereof include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2-cyclododecen-1-yl, 2-cycloeicosen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Among them, a C₄-C₁₂ cycloalkenyl group is preferable, and a C₄-C₈ cycloalkenyl group is particularly preferable.

In the present specification, the “C₄-C₁₂ cycloalkenyl group” means a cyclic alkenyl group having 4 to 12 carbon atoms, and examples thereof include 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2-cyclohepten-1-yl, 2-cycloocten-1-yl, 2-cyclononen-1-yl, 2-cyclodecen-1-yl, 2-cyclododecen-1-yl, 2,4-cyclopentadien-1-yl, 2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl and the like. Among them, a C₄-C₈ cycloalkenyl group is preferable.

In the present specification, the “C₃-C₂₀ cycloalkyl group”, “C₃-C₁₂ cycloalkyl group”, “C₄-C₂₀ cycloalkenyl group” and “C₄-C₁₂ cycloalkenyl group” are optionally fused with a benzene ring, and examples thereof include 1,2-dihydronaphthalen-1-yl, 1,2-dihydronaphthalen-2-yl, 1,2,3,4-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl, fluoren-9-yl, inden-1-yl and the like.

In the present specification, the “C₆-C₂₀ aromatic hydrocarbon group (the C₆-C₂₀ aryl group)” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 20 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl, acenaphthyl, naphthacenyl, biphenylyl and the like. Among them, a C₆-C₁₄ aromatic hydrocarbon group (a C₆-C₁₄ aryl group) is preferable, and a C₆-C₁₀ aromatic hydrocarbon group (a C₆-C₁₀ aryl group) is particularly preferable.

In the present specification, the “C₆-C₁₂ aromatic hydrocarbon group (the C₆-C₁₂ aryl group)” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 12 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl, acenaphthyl, biphenylyl and the like. Among them, a C₆-C₁₀ aromatic hydrocarbon group (a C₆-C₁₀ aryl group) is preferable.

In the present specification, the “C₆-C₁₀ aryl group” means a monocyclic or polycyclic (fused) hydrocarbon group having 6 to 10 carbon atoms and showing aromaticity, and examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.

In the present specification, the “C₇-C₁₄ aralkyl group” means a alkyl “C₁₋₄ group” substituted by “C₆-C₁₀ aryl group(s)”, and examples thereof include benzyl, 1-phenylethyl, 2-phenylethyl, (naphthyl-1-yl)methyl, (naphthyl-2-yl)methyl, 1-(naphthyl-1-yl)ethyl, 1-(naphthyl-2-yl)ethyl, 2-(naphthyl-1-yl)ethyl, 2-(naphthyl-2-yl)ethyl and the like.

In the present specification, the “C₁-C₁₂ alkoxy group” means a straight or branched chain alkoxy group having 1 to 12 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy and the like. Among them, a C₁-C₈ alkoxy group is preferable, and a C₁-C₄ alkoxy group is particularly preferable.

In the present specification, the “C₁-C₆ alkoxy group” means a straight or branched chain alkoxy group having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like. Among them, a C₁-C₄ alkoxy group is preferable.

In the present specification, the “C₁-C₁₂ alkylthio group” means a straight or branched chain alkylthio group having 1 to 12 carbon atoms, and examples thereof include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, heptylthio, octylthio, nonylthio, decylthio, undecylthio, dodecylthio and the like. Among them a C₁-C₈ alkylthio group is preferable, and a C₁-C₄ alkylthio group is particularly preferable.

In the present specification, the “aromatic heterocyclic group” means a monocyclic or polycyclic (fused) heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and showing aromaticity.

In the present specification, examples of the “monocyclic aromatic heterocyclic group” include furyl, thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl), thiadiazolyl (1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl), triazolyl (1,2,4-triazolyl, 1,2,3-triazolyl), tetrazolyl, triazinyl and the like. Among them, a 5- or 6-membered monocyclic aromatic heterocyclic group is preferable.

In the present specification, the “fused aromatic heterocyclic group” means the above-mentioned monocyclic aromatic heterocyclic group fused with a monocyclic aromatic ring (preferably a benzene ring or a monocyclic aromatic heterocycle), and examples thereof include quinolyl, isoquinolyl, quinazolyl, quinoxalyl, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzimidazolyl, benzotriazolyl, indolyl, indazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazopyridyl, thienopyridyl, pyrrolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, thienopyrazinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, thienopyrimidinyl, pyrazolothienyl and the like.

In the present specification, examples of the “monocyclic aromatic heterocycle” include furan, thiophene, pyridine, pyrimidine, pyridazine, pyrazine, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, oxadiazole (1,2,4-oxadiazole, 1,3,4-oxadiazole), thiadiazole (1,2,4-thiadiazole, 1,3,4-thiadiazole), triazole (1,2,4-triazole, 1,2,3-triazole), tetrazole, triazine and the like. Among them, a 5- or 6-membered monocyclic aromatic heterocycle is preferable.

In the present specification, the “C₁-C₁₂ fluorinated alkyl group” means a “C₁-C₁₂ alkyl group” substituted by fluorine atom(s). The number of the fluorine atoms is not particularly limited, and the C₁-C₁₂ fluorinated alkyl group may be perfluoro-substituted. Specific examples thereof include fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-fluorohexyl, 7-fluoroheptyl, 8-fluorooctyl, 9-fluorononyl, 10-fluorodecyl, 11-fluoroundecyl, 12-fluorododecyl and the like. Among them, a C₁-C₆ fluorinated alkyl group is preferable.

In the present specification, the “C₁-C₁₂ fluorinated alkyloxy group” means a “C₁₋₁₂ alkoxy group” substituted by fluorine atom(s). The number of the fluorine atoms is not particularly limited, and the C₁-C₁₂ fluorinated alkyloxy group may be perfluoro-substituted. Specific examples thereof include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy, 7-fluoroheptyloxy, 8-fluorooctyloxy, 9-fluorononyloxy, 10-fluorodecyloxy, 11-fluoroundecyloxy, 12-fluorododecyloxy and the like. Among them, a C₁-C₆ fluorinated alkyloxy group is preferable.

In the present specification, the “C₂-C₁₃ alkylcarbonyl group” means a group wherein a “C₁-C₁₂ alkyl group” is bonded to —C(═O)—, i.e., a “C₁-C₁₂ alkyl-carbonyl group”, and examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, hexylcarbonyl, heptylcarbonyl, octylcarbonyl, nonylcarbonyl, decylcarbonyl, undecylcarbonyl, dodecylcarbonyl and the like. Among them a C₂-C₉ alkylcarbonyl group is preferable, and a C₂-C₅ alkylcarbonyl group is particularly preferable.

In the present specification, the “C₂-C₁₃ alkoxycarbonyl group” means a group wherein a “C₁-C₁₂ alkoxy group” is bonded to —C═O—, i.e., a “C₁-C₁₂ alkoxy-carbonyl group”, and examples thereof include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, hexyloxycarbonyl, heptyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl and the like. Among them, a C₂-C₉ alkoxycarbonyl group is preferable, and a C₂-C₅ alkoxycarbonyl group is particularly preferable.

In the present specification, the “C₂-C₁₃ acyl group” is a residue obtained by removing a hydroxyl group from a C₂-C₁₃ carboxylic acid, and it means a “C₂-C₁₃ aliphatic acyl group” or a “C₇-C₁₃ aromatic acyl group”.

In the present specification, the “C₂-C₁₃ aliphatic acyl group” means a group wherein a “C₁-C₁₂ aliphatic hydrocarbon group” is bonded to —C═O—, i.e., a “C₁-C₁₂ aliphatic hydrocarbon-carbonyl group”, and examples thereof include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, propionoyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like. Among them, a C₂-C₁₃ alkylcarbonyl group is preferable, and a C₂-C₉ alkylcarbonyl group is particularly preferable.

In the present specification, the “C₇-C₁₃ aromatic acyl group” means a group wherein a “C₆-C₁₂ aromatic hydrocarbon group (a C₆-C₁₂ aryl group)” is bonded to —C═O—, i.e., a “C₆-C₁₂ aromatic hydrocarbon (a C₆-C₁₂ aryl)-carbonyl group”, and examples thereof include benzoyl, 1-naphthoyl, 2-naphthoyl and the like.

In the present specification, the “protected amino group” means an amino group protected by a “protecting group”. Examples of the “protecting group” include a C₁₋₆ alkyl group, a C₂₋₆ alkenyl group, a C₆₋₁₀ aryl group, a C₇₋₁₄ aralkyl group, a C₁₋₆ alkyl-carbonyl group, a C₁₋₆ alkoxy-carbonyl group, a C₂₋₆ alkenyl-oxycarbonyl group, a C₆₋₁₀ aryl-carbonyl group, a C₇₋₁₄ aralkyl-carbonyl group, a C₆₋₁₀ aryl-oxycarbonyl group, a C₇₋₁₄ aralkyl-oxycarbonyl group, a C₆₋₁₀ arylsulfonyl group, a benzhydryl group, a trityl group, a tri-C₁₋₆ alkylsilyl group, a 9-fluorenylmethyloxycarbonyl group, a phthaloyl group and the like. The above-mentioned protecting group is optionally substituted by a halogen atom, a C₁₋₆ alkyl group, a C₁₋₆ alkoxy group or a nitro group.

Specific examples of the protecting group include acetyl, trifluoroacetyl, pivaloyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, benzhydryl, trityl, phthaloyl, allyloxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl and the like.

In the present specification, the “C₁₋₆ alkyl-carbonyl group” means a group wherein a “C₁₋₆ alkyl group” is bonded to —C═O—.

In the present specification, the “C₁₋₆ alkoxy-carbonyl group” means a group wherein a “C₁₋₆ alkoxy group” is bonded to —C═O—.

In the present specification, the “C₂₋₆ alkenyl-oxycarbonyl group” means a group wherein a “C₂₋₆ alkenyl group” is bonded to the oxygen atom of —C(═O)O—.

In the present specification, the “C₆₋₁₀ aryl-carbonyl group” means a group wherein a “C₆₋₁₀ aryl group” is bonded to —C═O—.

In the present specification, the “C₇₋₁₄ aralkyl-carbonyl group” means a group wherein a “C₇₋₁₄ aralkyl group” is bonded to —C═O—.

In the present specification, the “C₆₋₁₀ aryl-oxycarbonyl group” means a group wherein a “C₆₋₁₀ aryl group” is bonded to the oxygen atom of —C(═O)O—.

In the present specification, the “C₇₋₁₄ aralkyl-oxycarbonyl group” means a group wherein a “C₇₋₁₄ aralkyl group” is bonded to the oxygen atom of —C(═O)O—.

In the present specification, the “C₆₋₁₀ arylsulfonyl group” means a group wherein a “C₆₋₁₀ aryl group” is bonded to —S(═O)₂—.

In the present specification, the “tri-C₁₋₆ alkylsilyl group” means —SiH₃ tri-substituted by “C₁-C₆ alkyl groups”.

Each group of the formulas (1)-(4) is explained below.

R¹ is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1 or a hydrogen atom. The number of the substituents for the C₁-C₂₀ hydrocarbon group is preferably 1 to 3. When it is 2 or more, these substituents may be the same or different.

R¹ is

preferably a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1,

more preferably a C₁-C₂₀ alkyl group optionally having substituent(s) selected from Group G1, a C₃-C₂₀ cycloalkyl group optionally having substituent(s) selected from Group G1 or a C₆-C₂₀ aryl group optionally having substituent(s) selected from Group G1,

further more preferably a C₁-C₁₂ alkyl group optionally having substituent(s) selected from Group G1, a C₃-C₁₂ cycloalkyl group optionally having substituent(s) selected from Group G1 or a C₆-C₁₂ aryl group optionally having substituent(s) selected from Group G1, still more preferably a C₁-C₈ alkyl group optionally having substituent(s) selected from Group G1, a C₃-C₈ cycloalkyl group optionally having substituent(s) selected from Group G1 or a C₆-C₁₀ aryl group optionally having substituent(s) selected from Group G1, particularly preferably a C₁-C₆ alkyl group optionally having substituent(s) selected from Group G1 (preferably a C₆-C₁₀ aryl group, a C₁-C₁₂ alkoxy group having C₆-C₁₀ aryl group(s)), a C₃-C₈ cycloalkyl group, a C₆-C₁₀ aryl group (preferably a phenyl group) optionally having substituent(s) selected from Group G1 (preferably a halogen atom, a C₁-C₆ alkoxy group, a C₁-C₆ fluorinated alkyl group).

Ar¹ and Ar² are each independently a phenyl group optionally having substituent(s) selected from Group G2, a C₁-C₁₂ chain hydrocarbon group, a C₃-C₁₂ alicyclic hydrocarbon group or a hydrogen atom. The number of the substituents for the phenyl group is preferably 1 to 3. When it is 2 or more, these substituents may be the same or different.

Ar¹ and Ar² are

preferably each independently a phenyl group optionally having substituent(s) selected from Group G2,

more preferably each independently a phenyl group optionally having C₁-C₁₂ fluorinated alkyl group(s),

further more preferably each independently a phenyl group optionally having C₁-C₄ fluorinated alkyl group(s),

still more preferably each independently a phenyl group optionally having trifluoromethyl group(s),

still more preferably both phenyl groups or both 3,5-bis(trifluoromethyl)phenyl groups,

particularly preferably both 3,5-bis(trifluoromethyl)phenyl groups.

R⁵ is a hydrogen atom, a fluorine atom, a hydroxyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ fluorinated alkyloxy group or a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group or a C₆-C₂₀ aryl group.

R⁵ is

preferably a hydroxyl group or a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above,

more preferably a hydroxyl group or a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group (preferably a methyl group), further more preferably a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group (preferably a methyl group), still more preferably a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₄ alkyl group (preferably a methyl group), particularly preferably a trimethylsilyloxy group.

Preferable combination of Ar¹, Ar² and R⁵ is as follows:

(1) An embodiment wherein Ar¹ and Ar² are each independently a phenyl group optionally having substituent(s) selected from Group G2, and R⁵ is a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are as defined above.

(2) An embodiment wherein Ar¹ and Ar² are each independently a phenyl group optionally having C₁-C₁₂ fluorinated alkyl group(s), and R⁵ is a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group (preferably a methyl group). (3) An embodiment wherein Ar¹ and Ar² are each independently a phenyl group optionally having C₁-C₄ fluorinated alkyl group(s), and R⁵ is a silyloxy group represented by —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₄ alkyl group (preferably a methyl group). (4) An embodiment wherein Ar¹ and Ar² are each independently a phenyl group optionally having trifluoromethyl group(s), and R⁵ is a trimethylsilyloxy group. (5) An embodiment wherein Ar¹ and Ar² are both phenyl groups or both 3,5-bis(trifluoromethyl)phenyl groups, and R⁵ is a trimethylsilyloxy group. (6) An embodiment wherein Ar¹ and Ar² are both 3,5-bis(trifluoromethyl)phenyl groups, and R⁵ is a trimethylsilyloxy group.

R² is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1, a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from Group G1, a C₁-C₁₂ alkylthio group optionally having substituent(s) selected from Group G1, a protected amino group, a heterocyclic group optionally having substituent(s) selected from Group G2 or a hydrogen atom.

R² is

preferably a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from Group G1 or a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from Group G1,

more preferably a C₁-C₁₂ alkyl group optionally having substituent(s) selected from Group G1 or a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from Group G1,

further more preferably a C₁-C₈ alkyl group optionally having substituent(s) selected from Group G1 or a C₁-C₈ alkoxy group optionally having substituent(s) selected from Group G1,

still more preferably a C₁-C₄ alkyl group optionally having substituent(s) selected from Group G1 or a C₁-C₄ alkoxy group optionally having substituent(s) selected from Group G1,

particularly preferably a C₁-C₄ alkyl group or a C₁-C₄ alkoxy group optionally having C₆-C₁₀ aryl group(s).

R^(X) is an amino-protecting group.

R^(X) is

preferably a C₆₋₁₀ arylsulfonyl group optionally having substituent(s) (preferably a C₁₋₆ alkyl group or a nitro group),

more preferably a benzenesulfonyl group optionally having C₁₋₆ alkyl group(s) or nitro group(s),

further more preferably a p-toluenesulfonyl group (a tosyl (Ts) group), an o-nitrobenzenesulfonyl group (an o-nosyl (o-Ns) group) or a p-nitrobenzenesulfonyl group (a p-nosyl (p-Ns) group),

particularly preferably a p-toluenesulfonyl group (a tosyl (Ts) group) or a p-nitrobenzenesulfonyl group (a p-nosyl (p-Ns) group).

Ar^(X) is a phenyl group optionally having substituent(s) selected from Group G2.

Ar^(X) is preferably a phenyl group.

In the present invention, optically active β-aminoaldehyde (3) is produced by a step of reacting imine compound (1-1) or a precursor thereof, i.e., sulfone compound (1-2) with aldehyde compound (2) in the presence of optically active pyrrolidine compound (4) as a catalyst (Mannich reaction step).

Sulfone compound (1-2) can be produced according to the method described in Synthesis 2000, 75. For example, when R^(X) is a substituted C₆₋₁₀ arylsulfonyl group (e.g. a tosyl group, an o-nosyl group or a p-nosyl group etc.), it can be produced by reacting the corresponding aldehyde (R¹CHO) with the corresponding C₆₋₁₀ arenesulfonamide and the corresponding sodium sulphinate (Ar^(X)SO₂Na) in the presence of formic acid. Imine compound (1-1) can be produced by eliminating —SO₂Ar^(X) from sulfone compound (1-2).

The use of Sulfone compound (1-2) is convenient since the Mannich reaction progresses together with elimination of SO₂Ar^(X).

The amount of aldehyde compound (2) to be used is preferably 1-10 mol, more preferably 3-7 mol, relative to imine compound (1-1) or sulfone compound (1-2), in view of yield, selectivity and economic efficiency.

The catalyst, optically active pyrrolidine compound (4) is preferably a pyrrolidine compound represented by the formula (4a):

wherein Ar¹, Ar² and * are as defined above, TMS is a trimethylsilyl group, and the carbon atom marked with * is an asymmetric carbon atom, in view of diastereoselectivity (when R² in aldehyde compound (2) is not a hydrogen atom), though depending on the kind of imine compound (1-1) or sulfone compound (1-2) and aldehyde compound (2). Among them, a pyrrolidine compound wherein Ar¹ and Ar² are each independently a phenyl group optionally having C₁-C₄ fluorinated alkyl group(s) is preferable, a pyrrolidine compound wherein Ar¹ and Ar² are each independently a phenyl group optionally having trifluoromethyl group(s) is more preferable, a pyrrolidine compound wherein Ar¹ and Ar² are both phenyl groups or both 3,5-bis(trifluoromethyl)phenyl groups is still more preferable, and a pyrrolidine compound wherein Ar¹ and Ar² are both 3,5-bis(trifluoromethyl)phenyl groups is particularly preferable.

The amount of optically active pyrrolidine compound (4) to be used is preferably 0.5-30 mol %, more preferably 1-20 mol %, particularly preferably 5-15 mol %, relative to imine compound (1-1) or sulfone compound (1-2), in view of yield and economic efficiency.

The Mannich reaction of the present invention is preferably carried out in the presence of a base. Examples of the base include sodium hydrogen carbonate, potassium hydrogen carbonate and the like. Among them, sodium hydrogen carbonate is preferable in view of economic efficiency.

The amount of the base to be used is preferably 1-10 mol, more preferably 1-5 mol, relative to imine compound (1-1) or sulfone compound (1-2), in view of yield and economic efficiency.

The Mannich reaction of the present invention is preferably carried out in a solvent. Examples of the solvent to be used in the present invention include aromatic hydrocarbon solvents (e.g., toluene, benzene, xylene); alcohol solvents (e.g., methanol, ethanol); halogenated hydrocarbon solvents (e.g., chloroform, dichloromethane, carbon tetrachloride); ether solvents (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane); nitrile solvents (e.g., acetonitrile); aprotic polar solvents (e.g., dimethylformamide, dimethylacetamide); water; mixed solvents thereof, and the like.

Among them, though depending on the kind of imine compound (1-1) or sulfone compound (1-2) and aldehyde compound (2), in view of enantioselectivity and diastereoselectivity (when R² in aldehyde compound (2) is not a hydrogen atom), ether solvents (preferably tetrahydrofuran, 1,4-dioxane, more preferably 1,4-dioxane), halogenated hydrocarbon solvents (preferably dichloromethane), water, and mixed solvents of water and a halogenated hydrocarbon solvent (preferably dichloromethane) are preferable, and in view of good yield, superior enantioselectivity and diastereoselectivity (when R² in aldehyde compound (2) is not a hydrogen atom), ether solvents (preferably tetrahydrofuran, 1,4-dioxane, more preferably 1,4-dioxane), water, and mixed solvents of water and a halogenated hydrocarbon solvent (preferably dichloromethane) are more preferable, and ether solvents (preferably tetrahydrofuran, 1,4-dioxane, more preferably 1,4-dioxane) and water are still more preferable, and 1,4-dioxane and water are particularly preferable.

When water is used, water containing an inorganic salt is preferably used in view of yield. Examples of the inorganic salt include sodium chloride, potassium chloride, sodium sulfate and the like. Among them, sodium chloride is preferable in view of economic efficiency. The water containing an inorganic salt is preferably used within the range from a 5 wt % aqueous solution to a saturated aqueous solution. When sodium chloride is used, a saturated aqueous solution thereof is particularly preferably used.

When the solvent is a mixed solvent of water and a halogenated hydrocarbon solvent, the amount of water to be used is preferably 0.3-5 mL, more preferably 0.5-2 mL, per 1 mL of the halogenated hydrocarbon solvent.

The amount of the solvent to be used is preferably 0.2-50 mL, more preferably 1-10 mL, per 1 mmol of imine compound (1-1) or sulfone compound (1-2).

The Mannich reaction of the present invention is carried out by a method of adding aldehyde compound (2) to a mixture of imine compound (1-1) or sulfone compound (1-2), optically active pyrrolidine compound (4), a base and a solvent; or the like.

The Mannich reaction of the present invention is preferably carried out within the range of 0-100° C., more preferably within the range of 0-40° C., though depending on the kind of imine compound (1-1) or sulfone compound (1-2) and aldehyde compound (2).

While the reaction time varies depending on the kind of imine compound (1-1) or sulfone compound (1-2) and aldehyde compound (2), and the reaction temperature, it is preferably 1-100 hr, more preferably 10-50 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Optically active β-aminoaldehyde compound (3) contained in thus obtained reaction mixture can be isolated by subjecting the reaction mixture to a post-treatment using a conventional method (e.g., neutralization, extraction, washing with water, distillation, crystallization etc.), and purified by subjecting optically active β-aminoaldehyde compound (3) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment using activated carbon, silica, alumina and the like, or chromatography treatment using silica gel column chromatography and the like.

Optically active β-aminoaldehyde compound (3) is not always stable, and, in some cases, it may be isomerized during isolation and/or purification from the reaction mixture. Therefore, the diastereo ratio (syn/anti ratio) and enantiomeric excess (ee(%)) of optically active β-aminoaldehyde compound (3) are desirably determined without isolation and/or purification after completion of the aldol reaction, but after conversion of optically active β-aminoaldehyde compound (3) to a compound free of isomerization during reaction, isolation and purification. In the present invention, optically active β-aminoaldehyde compound (3) is converted to a corresponding optically active amidoalcohol compound (an optically active amidoalcohol compound represented by the formula (5):

wherein R¹, R² and R^(X) are as defined above.

Optically active amidoalcohol compound (5) is produced by a step of reducing the reaction mixture after completion of the Mannich reaction which contains optically active β-aminoaldehyde compound (3), or optically active β-aminoaldehyde compound (3) without purification.

The reduction reaction is carried out using a reducing agent in a solvent.

Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium aluminum hydride and the like. Among them, sodium borohydride is preferable in view of yield and economic efficiency.

The amount of the reducing agent to be used is preferably 1-100 mol, preferably 5-15 mol, per 1 mol of optically active β-aminoaldehyde compound (3), in view of yield and economic efficiency.

Examples of the solvent to be used for the reduction reaction include alcohol solvents (e.g., methanol, ethanol, 2-propanol); water; mixed solvents thereof, and the like. Among them, alcohol solvents (e.g., methanol, ethanol) are preferable in view of yield and reactivity.

The amount of the solvent to be used is preferably 1-100 mL, more preferably 5-20 mL, per 1 g of optically active β-aminoaldehyde compound (3).

The reduction reaction is carried out by a method of adding a reducing agent to a solution prepared by dissolving optically active β-aminoaldehyde compound (3) in a solvent; a method of adding optically active β-aminoaldehyde compound (3) to a dispersion prepared by a reducing agent in a solvent; or the like. In view of yield and operability, the reaction is preferably carried out by a method of adding a reducing agent to a solution prepared by dissolving optically active β-aminoaldehyde compound (3) in a solvent.

The reduction reaction is preferably carried out within the range of −20-100° C., more preferably within the range of −10-30° C., though depending on the kind of optically active β-aminoaldehyde compound (3) and the reducing agent.

While the reaction time varies depending on the kind of optically active β-aminoaldehyde compound (3) and the reducing agent, and the reaction temperature, it is preferably 10 min-10 hr, more preferably 30 min-2 hr.

The progress of the reaction can be confirmed by an analysis means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.

Optically active amidoalcohol compound (5) contained in thus obtained reaction mixture can be isolated by subjecting the reaction mixture to a post-treatment using a conventional method (e.g., neutralization, extraction, washing with water, distillation, crystallization etc.), and purified by subjecting optically active amidoalcohol compound (5) to recrystallization treatment, extraction purification treatment, distillation treatment, adsorption treatment using activated carbon, silica, alumina and the like, or chromatography treatment using silica gel column chromatography and the like.

The diastereo ratio (syn/anti ratio) and enantiomeric excess of the obtained optically active amidoalcohol compound (5) are determined. The measured diastereo ratio (syn/anti ratio) and enantiomeric excess correspond to those of optically active β-aminoaldehyde compound (3).

When R² in aldehyde compound (2) is not a hydrogen atom, in the Mannich reaction step of the present invention, the anti-form of optically active β-aminoaldehyde compound (3) is preferentially obtained. The diastereoselectivity showing a diastereo ratio (syn/anti ratio) of, for example, 50/50 or more, or, for example, 20/80 or more, is available.

In the Mannich reaction step of the present invention, when pyrrolidine compound (4a) wherein the absolute configuration of C* is S-configuration, i.e., a pyrrolidine compound represented by the formula (4a-S):

wherein Ar¹ and Ar² are as defined above, and TMS is a trimethylsilyl group, is used as a catalyst, optically active β-aminoaldehyde compound (3) wherein the absolute configuration of C* is S-configuration, i.e., an optically active β-aminoaldehyde compound represented by the formula (3R):

wherein R¹, R² and Rx are as defined above, is preferentially obtained.

On the other hand, pyrrolidine compound (4a) wherein the absolute configuration of C* is R-configuration, i.e., a pyrrolidine compound represented by the formula (4a-R):

wherein Ar¹ and Ar² are as defined above, and TMS is a trimethylsilyl group, is used as a catalyst, optically active β-aminoaldehyde compound (3) wherein the absolute configuration of C* is R-configuration, i.e., an optically active β-aminoaldehyde compound represented by the formula (3S):

wherein R¹, R² and Rx are as defined above, is preferentially obtained.

Therefore, in the Mannich reaction step of the present invention, the enantioselectivity showing an enantiomeric excess of, for example, 50ee % or more, or, for example, 80ee % or more, is available.

Example

The present invention is explained in detail in the following by referring to Examples.

All reactions were carried out under argon atmosphere and monitored by thin-layer chromatography using Merck 60 F254 precoated silica gel plates (0.25 mm thickness).

FT-IR spectra were recorded on a JASCO FT/IR-410 spectrometer.

¹H and ¹³C NMR spectra were recorded on a Bruker AM400 (400 MHz for ¹H NMR, 100 MHz for ¹³C NMR) instrument. Data for ¹H NMR are reported as chemical shift (δ ppm), multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet), coupling constant (Hz), integration and assignment. Data for ¹³C NMR are reported as chemical shift. High-resolution mass spectral analyses (HRMS) were carried out using Bruker ESI-TOF MS.

All liquid aldehydes and solvents were distilled before use.

Preparative thin layer chromatography was performed using Wakogel B-5F purchased from Wako Pure Chemical Industries (Tokyo, Japan). Flash chromatography was performed using silica gel 60N of Kanto Chemical Co. Int. (Tokyo, Japan).

HPLC analysis was performed on a HITACHI Elite LaChrom Series HPLC, while UV detection was monitered at appropriate wavelength respectively, using CHIRALCEL OJ-H (0.46 cm×25 cm), CHIRALPAK AD-H (0.46 cm×25 cm), CHIRALPAK AS-H (0.46 cm×25 cm), CHIRALPAK IA (0.46 cm×25 cm), CHIRALPAK IB (0.46 cm×25 cm) and CHIRALPAK IC (0.46 cm×25 cm).

Reference Examples 1-1-1-7 Production of Sulfone Compound

A mixture of aldehyde (5 mmol), arenesulfonamide (5 mmol), and sodium benzenesulfinate dihydrate (5.5 mmol) in formic acid (7.5 mL) and H₂O (7.5 mmol) was stirred at 23° C. for 12 h. The resulting white precipitate was collected by filtration, washed successively with H₂O (10 mL) and hexane (10 mL), and dissolved in CH₂Cl₂ (30 mL), and the solution was dried over Na₂SO₄, and filtration. The solvent was evaporated, and to the residue was added hexane. The resulting precipitate was collected by filtration, and dried under reduced pressure to give the corresponding sulfone compound.

N-(3-phenyl-1-(phenylsulfonyl)propyl)-p-toluenesulfonamide Reference Example 1-1

¹H NMR (CDCl₃, 400 MHz): δ 1.90-2.01 (1H, m), 2.40 (3H, s), 2.43-2.71 (3H, m), 4.61 (1H, ddd, J=4.0, 9.6, 8.8 Hz), 5.49 (1H, br-s), 7.04 (2H, d, J=6.8 Hz), 7.17-7.28 (5H, m), 7.46-7.55 (4H, m), 7.65 (1H, t, J=7.6 Hz), 7.82 (2H, d, J=7.6 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 21.5, 30.3, 31.2, 73.1, 126.4, 126.8, 128.3, 128.6, 129.1, 129.6, 129.7, 134.2, 135.8, 137.6, 139.6, 143.9;

IR (KBr): ν 3321, 2955, 2928, 1448, 1341, 1299, 1160, 1145, 1081, 959, 813, 751 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₂H₂₃O₄S₂NNa]): 452.0961. found 452.0969.

N-(3-methyl-1-(phenylsulfonyl)butyl)-p-toluenesulfonamide Reference Example 1-2

¹H NMR (CDCl₃, 400 MHz): δ 0.77 (3H, dd, J=2.0, 6.4 Hz), 0.85 (3H, dd, J=1.2, 6.4 Hz), 1.43-1.53 (1H, m), 1.59 (1H, ddd, J=4.0, 10.8, 14.4 Hz), 1.93 (1H, ddd, J=3.2, 10.0, 13.6 Hz), 2.39 (3H, s), 4.66 (1H, dt, J=3.2, 10.4 Hz), 5.61-5.77 (br-m), 7.20 (2H, d, J=8.4 Hz), 7.52 (2H, t, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz), 7.65 (1H, t, J=7.6 Hz), 7.84 (2H, d, J=7.2 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 21.0, 21.5, 13.2, 24.0, 37.0, 72.7, 126.7, 129.1, 129.5, 129.7, 134.2, 135.6, 137.8, 143.7;

IR (KBr): ν 3239, 2952, 2871, 1596, 1459, 1330, 1286, 1071, 906, 812, 676 cm⁻¹; HRMS (ESI): [M+Na] calculated for ([C₁₈H₂₃O₄S₂NNa]): 404.0961. found 404.0946.

N-(2-methyl-1-(phenylsulfonyl)propyl)-p-toluenesulfonamide Reference Example 1-3

¹H NMR (CDCl₃, 400 MHz): δ 0.85 (3H, d, J=6.8 Hz), 1.04 (3H, d, J=6.8 Hz), 2.39 (3H, s), 2.60-2.77 (1H, m), 4.53 (1H, dd, J=2.8, 10.8 Hz), 5.49 (1H, br-d, J=10.8), 7.17 (2H, d, J=8.4 Hz), 7.48 (2H, br-b, J=8.0 Hz), 7.63 (1H, br-t, J=7.2 Hz), 7.84 (2H, br-d, J=7.2 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 16.6, 20.9, 21.5, 27.6, 77.6, 126.6, 129.1, 129.3, 129.6, 134.0, 137.1, 138.0, 143.6;

IR (KBr): ν 3300, 2967, 2932, 1470, 1419, 1342, 1307, 1166, 1135, 1083, 1055, 887, 669 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₇H₂₁O₄S₂NNa]): 390.0804. found 390.0798.

N-(cyclohexyl(phenylsulfonyl)methyl)-p-toluenesulfonamide Reference Example 1-4

¹H NMR (CDCl₃, 400 MHz): δ 0.90-1.09 (3H, m), 1.28 (2H, tq, J=2.8, 12.8 Hz), 1.53-1.79 (3H, m), 2.01 (1H, br-d, J=12.4 Hz), 2.40 (4H, s), 4.48 (1H, dd, J=3.2, 10.8 Hz), 5.25 (1H, d, J=10.8 Hz), 7.17 (2H, d, J=8.4 Hz), 7.42-7.49 (4H, m), 7.62 (1H, t, J=7.6 Hz), 7.80 (2H, br-d, J=7.6 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 21.4, 25.4, 25.5, 26.0, 27.1, 30.8, 37.2, 77.7, 124.9, 126.3, 126.5, 128.9, 129.0, 129.2, 129.4, 129.5, 133.8, 136.9, 137.9, 143.4; IR (KBr): ν 3301, 2934, 2854, 1446, 1337, 1304, 1162, 1146, 1079, 751, 676 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₀H₂₅O₄S₂NNa]): 430.1117. found 430.1125.

N-(2-phenyl-1-(phenylsulfonyl)ethyl)-p-toluenesulfonamide Reference Example 1-5

¹H NMR (CDCl₃, 400 MHz): δ 2.32 (3H, s), 2.30 (1H, dd, J=10.4, 14.4 Hz), 3.60 (1H, dd, J=3.6, 14.4 Hz), 4.85 (1 h, dt, J=3.6, 10.0 Hz), 6.06 (1H, br-s), 6.92 (2H, d, J=8.0 Hz), 6.99-7.10 (5H, m), 7.14 (2H, d, J=8.0 Hz), 7.59 (2H, t, J=7.2 Hz), 7.70 (1H, t, J=7.2 Hz), 8.02 (2H, br-d, J=7.6 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 21.4, 33.6, 75.4, 126.1, 126.9, 128.6, 129.1, 129.5, 129.6, 130.1, 134.1, 134.4, 135.5, 137.4, 143.0;

IR (KBr): ν 3251, 3031, 2921, 1597, 14977, 1449, 1427, 1337, 1314, 1161, 1076, 732, 666 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₁H₂₁O₄S₂NNa]): 438.0804. found 438.0784.

N-(2-benzyloxy-1-(phenylsulfonyl)ethyl)-p-toluenesulfonamide Reference Example 1-6

¹H NMR (CDCl₃, 400 MHz): δ 2.37 (3H, s), 3.65 (1H, dd, J=4.0, 10.8 Hz), 4.05 (1H, dd, J=3.6, 10.8 Hz), 4.36 (1H, d, J=12.0 Hz), 4.41 (1H, d, J=12.0 Hz), 4.67-4.75 (1H, m), 5.96 (1H, br-s), 7.12-7.18 (4H, m), 7.27-7.32 (3H, m), 7.46 (2H, t, J=7.6 Hz), 7.56-7.65 (3H, m), 7.81 (2 h, d, J=7.6 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 21.5, 65.7, 72.8, 73.5, 126.9, 127.8, 127.9, 128.3, 128.9, 129.5, 129.6, 134.1, 136.2, 136.6, 137.3, 143.8;

IR (KBr): ν 3289, 3248, 2863, 1446, 1308, 1164, 1137, 1081, 949, 811, 666, 549 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₂H₂₃O₅S₂NNa]): 468.0910. found 468.0917.

N-(cyclohexyl(phenylsulfonyl)methyl)-p-nitrobenzenesulfonamide Reference Example 1-7

¹H NMR (CDCl₃, 400 MHz): δ 0.98-1.13 (3H, m), 1.21-1.35 (2H, m), 1.57-1.81 (4H, m), 1.99-2.08 (1H, m), 2.33 (1H, tq, J=12.0, 3.2 Hz), 4.54 (1H, dd, J=2.8, 10.8 Hz), 5.65 (1H, d, J=10.8 Hz), 7.46 (2H, t, J=8.0 Hz), 7.63 (1H, t, J=7.6 Hz), 7.74-7.80 (3H, m), 8.21 (2H, br-d, J=8.8 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 25.5, 26.0, 26.9, 31.1, 37.5, 77.2, 77.7, 124.3, 127.9, 129.1, 129.3, 134.3, 137.0, 146.2, 150.0;

IR (KBr): ν 3276, 2933, 2858, 1537, 1445, 1352, 1306, 1171, 1148, 1079, 851, 740 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₉H₂₂O₆S₂N₂Na]): 461.0811. found 461.0823.

Examples 1-1-1-8

To a mixture of the sulfone compound obtained in Reference Example 1-1 (0.2 mmol), pyrrolidine compound (12.0 mg, 0.02 mmol) as a catalyst and NaHCO₃ (50.4 mg, 0.6 mmol) in the solvent shown in Table 1 (0.4 mL) was added propanal (1.0 mmol) at 10° C. The reaction mixture was stirred at the temperature shown in Table 1 for 20 hr (stirred for 48 hr in Example 1-8), and the reaction was quenched by addition of aqueous NaHCO₃. The reaction mixture was extracted with chloroform (3×10 mL), and the combined organic layer were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane=1:7) to give N-((2R,3R)-2-methyl-1-oxo-5-phenylpentan-3-yl)-p-toluenesulfonamide. The yield is shown in Table 1. The syn/anti ratio was determined by ¹H-NMR spectrum after conversion to the corresponding amidoalcohol by reduction with NaBH₄ (according to the method shown in Reference Example 2). The enantiomeric excess was determined by HPLC equipped with CHIRALPAK IB column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=14.9 min, the retention time of the major enantiomer=13.3 min), after conversion to the corresponding amidoalcohol by reduction with NaBH₄ (according to the method shown in Reference Example 2). The syn/anti ratio and enantiomeric excess are shown in Table 1.

TABLE 1 Temperature Yield ee Example Solvent (° C.) (%) anti:syn (%) 1-1 CH₂Cl₂ 0 38 76:24 97 1-2 THF 0 52 95:5  98 1-3 1,4-dioxane 0 62 92:8  98 1-4 H₂O 0 41 93:7  96 1-5 saturated brine 0 60 89:11 96 1-6 saturated brine/CH₂Cl₂ 0 49 >95:5    97 (1/1) (volume ratio) 1-7 saturated brine 10 76 84:16 94 1-8 1,4-dioxane 10 79 88:12 96

Example 2-1-2-14

To a mixture of the sulfone compound obtained in Reference Examples 1-1-1-7 or the corresponding imine compound (0.2 mmol, used in Examples 2-10-2-14), pyrrolidine compound (12.0 mg, 0.02 mmol) as a catalyst and NaHCO₃ (50.4 mg, 0.6 mmol, not used in Example 2-10) in saturated brine (0.4 mL) or 1,4-dioxane (0.4 mL) was added the corresponding aldehyde (1.0 mmol) at 10° C. The reaction mixture was stirred (stirred for 20 hr when brine was used as a solvent, and stirred for 48 hr when 1,4-dioxane was used as a solvent), and the reaction was quenched by the addition of aqueous NaHCO₃. The reaction mixture was extracted with chloroform (3×10 mL), and the combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc:hexane=1:7) to give the corresponding β-aminoaldehyde compound. The yield is shown in Table 2. The syn/anti ratio was determined by ¹H-NMR spectrum after conversion to the corresponding amidoalcohol by reduction with NaBH₄ (according to the method shown in Reference Example 2). The enantiomeric excess was determined by chiral HPLC after conversion to the corresponding amidoalcohol by reduction with NaBH₄ (according to the method shown in Reference Example 2). The syn/anti ratio and enantiomeric excess are shown in Table 2. In Examples 2-8, 2-9, 2-11-2-14, the mixture after completion of the Mannich reaction was reduced with NaBH₄ (according to the method shown in Reference Example 2) to convert to the corresponding amidoalcohol, and the amidoalcohol was isolated.

N-((2R,3R)-2-methyl-1-oxo-5-phenylpentan-3-yl)-p-toluenesulfonamide Example 2-1

¹H NMR (CDCl₃, 400 MHz): δ 1.10 (3, d, J=7.2 Hz), 1.57-1.77 (2H, m), 2.32-2.52 (5H, m), 2.68 (1H, dq, J=4.0, 7.2 Hz), 3.55-3.64 (1H, m), 5.09 (1H, d, J=8.8 Hz), 6.96 (2H, d, J=7.2 Hz), 7.13-7.25 (3H, m), 7.30 (2H, d, J=8.4 Hz), 9.53 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 9.81, 21.5, 32.1, 34.3, 49.9, 54.2, 126.1, 127.0, 128.2, 128.4, 129.8, 138.1, 140.6, 143.6, 203.1;

IR (neat): ν 3279, 3028, 2929, 1721, 1454, 1326, 1160, 1092, 702, 666 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₉H₂₃NNaO₃S]): 368.1291. found 368.1308;

[α]_(D) ²⁰° C. +17.1 (c 0.35, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK IB column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=14.9 min, the retention time of the major enantiomer=13.3 min).

N-((2R,3R)-2,5-dimethyl-1-oxohexan-3-yl)-p-toluenesulfonamide Example 2-2

¹H NMR (CDCl₃, 400 MHz): δ 0.64 (3H, d, J=6.8 Hz), 0.76 (3H, d, J=6.8 Hz), 1.10 (3H, d, J=Hz), 1.15-1.27 (1H, m), 1.30-1.42 (2H, m), 2.42 (3H, s), 2.69 (1H, dq, J=3.2, 7.2 Hz), 3.60-3.68 (1H, m), 4.82 (1H, d, J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.4 Hz), 9.57 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 9.33, 21.5, 21.6, 22.9, 24.5, 41.7, 50.1, 52.3, 127.1, 129.7, 138.0, 143.5, 203.2;

IR (neat): ν 3279, 2958, 2871, 1719, 1463, 1427, 1330, 1281, 1160, 1093, 816, 667, 552 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₅H₂₃NNaO₃S]): 320.1291. found 320.1293;

[α]_(D) ²⁰° C. +19.5 (c 1.61, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK IA column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=10.5 min, the retention time of the major enantiomer=12.2 min).

N-((2R,3R)-2,4-dimethyl-1-oxopentan-3-yl)-p-toluenesulfonamide Example 2-3

¹H NMR (CDCl₃, 400 MHz): δ 0.76 (3H, d, J=6.8 Hz), 0.77 (3H, d, J=6.8 Hz), 1.06 (3H, d, J=7.2 Hz), 1.73-1.84 (1H, m), 2.41 (3H, s), 2.66 (1H, ddq, J=1.6, 6.8, 7.2 Hz), 3.34 (1H, ddd, J=4.4, 6.8, 9.2 Hz), 5.02 (1H, d, J=9.2 Hz), 7.28 (2H, d, J=8.0 Hz), 7.74 (2H, d, J=8.0 Hz), 9.57 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 11.5, 18.8, 20.2, 21.5, 30.9, 48.7, 61.0, 126.9, 129.6, 138.6, 143.3, 203.6;

IR (neat): ν 3290, 2967, 1719, 1326, 1160, 1092, 815, 667, 549 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₄H₂₁NNaO₃S]): 306.1134. found 306.1146;

[α]_(D) ²¹° C. +32.7 (c 1.33, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK IA column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=12.1 min, the retention time of the major enantiomer=22.5 min).

N-((2R,3R)-2,4-dimethyl-1-oxopentan-3-yl)-p-toluenesulfonamide Example 2-4

¹H NMR (CDCl₃, 400 MHz): δ 0.68-0.87 (2H, m), 0.95-1.15 (6H, In), 1.33-1.47 (2H, m), 1.53-1.70 (4H, m), 2.41 (3H, s), 2.66 (1H, dq, J=1.2, 4.0 Hz), 3.36 (1H, ddd, J=4.0, 7.2, 9.2 Hz), 5.07 (1H, d, J=9.2 Hz), 7.27 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 9.55 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 11.2, 21.5, 25.9, 26.0, 26.1, 29.4, 30.6, 40.6, 48.4, 60.3, 126.9, 129.5, 138.6, 143.2, 203.6;

IR (neat): ν 3289, 2928, 2853, 1721, 1448, 1326, 1160, 1092, 815, 667 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₇H₂₅NNaO₃S]): 346.1447. found 346.1451;

[α]_(D) ²²° C. +24.8 (c 0.36, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK AD-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=13.7 min, the retention time of the major enantiomer=14.9 min).

N-((2R,3R)-2-methyl-1-oxo-4-phenylbutan-3-yl)-p-toluenesulfonamide Example 2-5

¹H NMR (CDCl₃, 400 MHz): δ 1.18 (3H, d, J=7.6 Hz), 2.40 (3H, s), 2.57 (1H, dd, J=7.2, 13.6 Hz), 2.68-2.77 (3H, m), 3.70 (1H, dq, J=3.6, 8.0 Hz), 5.03 (1H, d, J=8.0 Hz), 6.90-6.97 (2H, m), 7.14-7.22 (5H, m), 7.58 (2H, d, J=8.4 Hz), 9.57 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 10.2, 21.5, 38.6, 48.3, 56.1, 126.8, 126.9, 128.7, 129.0, 129.6, 136.9, 137.4, 143.2, 203.4;

IR (neat): ν 3285, 2925, 1719, 1456, 1328, 1159, 1092, 701, 666, 550 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₈H₂₀NNaO₃S]): 330.1147. found 330.1158;

[α]_(D) ²²° C. +74.9 (c 0.33, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK IA column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=14.8 min, the retention time of the major enantiomer=16.5 min).

N-((2R,3S)-4-benzyloxy-2-methyl-1-oxobutan-3-yl)-p-toluenesulfonamide Example 2-6

¹H NMR (CDCl₃, 400 MHz): δ 1.05 (3H, d, J=7.2 Hz), 2.41 (3H, s), 2.70-2.78 (1H, m), 3.27 (1H, dd, J=5.6, 9.6 Hz), 3.36 (1H, dd, J=4.0, 9.6 Hz), 3.61-3.68 (1H, m), 4.32 (2H, s), 5.23 (1H, br-d, J=8.8 Hz), 7.18 (2H, d, J=7.2 Hz), 7.24 (2H, d, J=8.4 Hz), 7.28-7.37 (3H, m), 7.71 (2H, d, J=8.0 Hz), 9.58 (1H, d, J=1.2 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 10.6, 21.5, 47.6, 54.2, 69.1, 73.3, 127.0, 127.7, 128.0, 128.5, 129.7, 137.2, 137.7, 143.5, 202.6;

IR (neat): ν 3278, 2979, 2927, 2871, 1723, 1454, 1332, 1162, 1092, 826, 700, 667 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₉H₂₃NNaO₄S]): 384.1240. found 384.1244;

[α]_(D) ²²° C. −13.3 (c 0.34, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALCEL OJ-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, anti isomer: the retention time of the minor enantiomer=49.7 min, the retention time of the major enantiomer=32.5 min, syn isomer: the retention time of the minor enantiomer=26.8 min, the retention time of the major enantiomer=40.7 min).

N-(2R,3R)-2-ethyl-1-oxo-5-phenylpentan-3-yl)-p-toluenesulfonamide Example 2-7

¹H NMR (CDCl₃, 400 MHz): δ 0.92 (3H, t, J=7.6 Hz), 1.42-1.54 (1H, m), 1.60-1.81 (3H, m), 2.30-2.50 (5H, m), 3.52-3.60 (1H, m), 5.07 (1H, br-d, J=9.6 Hz), 6.96 (2H, d, J=7.2 Hz), 7.12-7.33 (5H, m), 7.73 (2H, d, J=8.0 Hz), 9.56 (1H, s);

¹³C NMR (CDCl₃, 100 MHz): δ 12.1, 18.9, 21.5, 32.3, 35.0, 52.8, 56.3, 126.1, 127.0, 128.2, 128.4, 129.7, 138.3, 140.6, 143.4, 203.7;

IR (neat): ν 3280, 2963, 2933, 2875, 1718, 1455, 1328, 1160, 1092, 816, 701, 666 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₀H₂₅NNaO₃S]): 382.1447. found 382.1429;

[α]_(D) ²³° C. +36.7 (c 1.45, CHCl₃);

The enantiomeric excess of the corresponding amidoalcohol after reduction was determined by HPLC equipped with CHIRALPAK IA column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=12.7 min, the retention time of the major enantiomer=26.5 min).

N-((1R,2R)-3-cyclohexyl-3-hydroxy-2-methylpropan-1-yl)-p-nitrobenzenesulfonamide Example 2-8

¹H NMR (CDCl₃, 400 MHz): δ 0.69-0.85 (2H, m), 0.90 (3H, t, J=6.8 Hz), 0.95-1.20 (3H, m), 1.35-1.53 (2H, m), 1.55-1.74 (5H, m), 1.76-1.87 (1H, m), 3.19 (1H, dt, J=9.2, 6.4 Hz), 3.51 (1H, dd, J=3.6, 11.2 Hz), 3.89 (1H, dd, J=3.2, 11.2 Hz), 5.39 (1H, br-d, J=9.2 Hz), 8.04 (2H, d, J=8.8 Hz), 8.33 (2H, d, J=8.8 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 15.8, 26.1, 26.2, 28.5, 31.0, 35.7, 40.5, 63.2, 64.7, 124.1, 128.1, 147.8, 149.7;

IR (neat): ν 3526, 3303, 2929, 2854, 1530, 1449, 1350, 1309, 1162, 1092, 854, 738 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₆H₂₄N₂O₅SNa]): 379.1298. found 379.1302; [α]_(D) ²⁵° C. −0.3 (c 0.78, CHCl₃);

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AD-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=22.7 min, the retention time of the major enantiomer=31.5 min).

N-((1R,2R)-2-benzyloxy-1-cyclohexyl-3-hydroxypropan-1-yl)-p-nitrobenzenesulfonamide Example 2-9

¹H NMR (CDCl₃, 400 MHz): δ 0.86-1.05 (2H, m), 1.16-1.22 (3H, m), 1.42-1.58 (2H, m), 1.59-1.70 (2H, m), 1.71-1.78 (1H, m), 1.87 (1H, br-d, J=12.8 Hz), 3.43 (1H, dt, J=4.8, 3.2 Hz), 3.56 (1H, ddd, J=4.8, 7.2, 9.2 Hz), 3.75 (1H, dd, J=3.2, 12.4 Hz), 3.81 (1H, dd, J=3.2, 12.4 Hz), 4.33 (1H, d, J=11.6 Hz), 4.37 (1H, d, J=11.6 Hz), 5.62 (1H, d, J=9.2 Hz), 7.13 (2H, dd, J=2.8, 7.2 Hz), 7.25-7.30 (3H, m), 7.95 (2H, br-d, J=8.8 Hz), 8.10 (2H, br-d, J=8.8 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 25.9, 26.01, 26.04, 29.2, 30.7, 39.5, 60.8, 60.9, 71.5, 77.3, 123.8, 127.7, 128.0, 128.1, 128.5, 137.3, 147.6, 149.4;

[α]_(D) ²⁵° C. −37.5 (c 0.35, CHCl₃);

IR (neat): ν 3524, 3298, 2928, 2854, 1529, 1452, 1349, 1310, 1162, 1093, 854, 738 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₂₂H₂₈N₂O₆SNa]): 471.1560. found 471.1550; The enantiomeric excess was determined by HPLC equipped with CHIRALPAK IC column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=42.6 min, the retention time of the major enantiomer=34.8 min).

N-((2R,3S)-2-methyl-1-oxo-3-phenylpropan-3-yl)-p-toluenesulfonamide Example 2-10

¹H NMR (CDCl₃, 400 MHz): δ 0.98 (3H, d, J=7.2 Hz), 2.32 (3H, s), 2.80 (1H, d of quint, J=2.4, 7.2 Hz), 4.54 (1H, t, J=8.4 Hz), 5.74 (1H, d, J=8.8 Hz), 6.96-7.02 (2H, m), 7.05 (2H, d, J=8.4 Hz), 7.09-7.15 (3H, m), 7.47 (2H, d, J=8.0 Hz), 9.62 (1H, d, J=2.4 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 11.8, 21.4, 51.9, 59.1, 126.9, 127.0, 127.7, 128.5, 129.2, 137.3, 138.0, 143.1, 203.1;

IR (neat): ν 3263, 2974, 2931, 2874, 2712, 1731, 1457, 1322, 1158, 1091, 913, 703, 671, 566 cm⁻¹.

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AS-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=15.4 min, the retention time of the major enantiomer=23.3 min).

N-((1S,2R)-3-hydroxy-2-methyl-1-phenylpropan-1-yl)-p-toluenesulfonamide Example 2-11

¹H NMR (CDCl₃, 400 MHz): δ 0.78 (3H, d, J=7.2 Hz), 1.88-2.00 (1H, m), 2.27 (1H, br-s), 2.34 (3H, s,), 3.55 (1H, dd, J=4.4, 11.2 Hz), 3.93 (1H, dd, J=3.2, 11.2 Hz), 4.18 (1H, t, J=8.4 Hz), 5.77 (1H, br-d, J=7.6 Hz), 6.91-6.96 (2H, m), 7.08 (2H, d, J=8.4 Hz), 7.10-7.15 (3H, m), 7.48 (2H, br-d, J=8.2 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 14.5, 21.4, 40.9, 61.5, 64.9, 126.8, 127.1, 127.3, 128.3, 129.2, 137.4, 140.1, 143.0;

IR (neat): ν 3509, 3280, 2925, 1600, 1456, 1158, 1092, 1030, 812, 703, 669 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₇H₂₁NO₃SNa]): 342.1134. found 342.1148;

[α]_(D) ²⁶° C. −39.5 (c 0.52, CHCl₃);

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AS-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=15.4 min, the retention time of the major enantiomer=23.3 min).

N-((1S,2R)-3-hydroxy-1-(p-methoxyphenyl)-2-methylpropan-1-yl)-p-toluenesulfonamide Example 2-12

¹H NMR (CDCl₃, 400 MHz): δ 0.75 (3H, d, J=6.8 Hz), 1.86-1.92 (1H, m), 2.35 (3H, s), 3.55 (1H, dd, J=4.4, 11.2 Hz), 3.74 (3H, s), 3.93 (1H, dd, J=3.2, 11.2 Hz), 4.13 (1H, t, J=8.0 Hz), 5.70 (1H, br-d, J=7.6 Hz), 6.65 (2H, br-d, J=8.8 Hz), 6.84 (2H, br-d, J=8.8 Hz), 7.10 (2H, d, J=8.0 Hz), 7.49 (2H, d, J=8.4 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 14.5, 21.4, 41.0, 55.2, 61.0, 65.0, 113.7, 127.1, 128.0, 129.2, 132.2, 137.5, 142.9, 158.8;

IR (neat): ν 3734, 3522, 2962, 2932, 1613, 1514, 1456, 1319, 1248, 1157, 1034, 814, 667 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₈H₂₃NO₄SNa]): 372.1240. found 372.1239;

[α]_(D) ²⁷° C. −53.5 (c 0.81, CHCl₃);

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AS-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=23.2 min, the retention time of the major enantiomer=52.6 min).

N-((1S,2R)-1-(p-bromophenyl)-3-hydroxy-2-methylpropan-1-yl)-p-toluenesulfonamide Example 2-13

¹H NMR (CDCl₃, 400 MHz): δ 0.75 (3H, d, J=6.8 Hz), 1.85-1.96 (1H, m), 2.37 (3H, s), 2.46 (1H, br-s), 3.55 (1H, dt, J=11.2, 4.8 Hz), 3.83 (1H, dt, J=11.2, 3.6 Hz), 4.18 (1H, t, J=8.0 Hz), 6.31 (1H, br-d, J=7.2 Hz), 6.86 (2H, d, J=8.0 Hz), 7.10 (2H, d, J=8.0 Hz), 7.22 (2H, d, J=8.4 Hz), 7.47 (2H, d, J=8.4 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 14.4, 21.4, 40.5, 61.4, 65.1, 121.1, 127.0, 128.8, 129.3, 131.3, 137.3, 139.1, 143.2;

IR (neat): ν 3488, 3274, 2964, 2927, 2883, 1597, 1489, 1456, 1322, 1158, 1092, 813, 661, 570 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₇H₂₀BrNO₃SNa]): 420.0239. found 420.0225; [α]_(D) ²⁶° C. −54.4 (c 0.36, CHCl₃);

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AS-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=14.9 min, the retention time of the major enantiomer=27.6 min).

N-((1S,2R)-3-hydroxy-2-methyl-1-(p-trifluoromethylphenyl)propan-1-yl)-p-toluenesulfonamide Example 2-14

¹H NMR (CDCl₃, 400 MHz): δ 0.80 (3H, d, J=6.8 Hz), 1.90-2.01 (1H, m), 2.24 (1H, t, J=4.8 Hz), 2.32 (3H, s), 3.57 (1H, dt, J=10.8, 5.6 Hz), 3.82 (1H, dt, J=10.8, 3.2 Hz), 4.32 (1H, t, J=7.6 Hz), 6.32 (1H, br-d, J=6.8 Hz), 7.05 (2H, d, J=8.0 Hz), 7.12 (2H, d, J=8.0 Hz), 7.35 (2H, d, J=8.0 Hz), 7.44 (8.4 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 14.5, 21.2, 40.4, 61.7, 65.2, 124.0 (q, J=270.0 Hz), 125.0 (q, J=4.0 Hz), 127.0, 127.6, 129.2, 129.3 (q, J=32.0 Hz), 137.2, 143.2, 143.9;

IR (neat): ν 3459, 3178, 2927, 1619, 1599, 1455, 1421, 1161, 1067, 1043, 814 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₈H₂₀F₃NO₃SNa]): 410.1008. found 410.1001 [α]_(D) ²⁶° C. −33.3 (c 0.36, CHCl₃);

The enantiomeric excess was determined by HPLC equipped with CHIRALPAK AS-H column (^(i)PrOH:hexane=1:10) (1.0 mL/min, the retention time of the minor enantiomer=10.0 min, the retention time of the major enantiomer=20.8 min).

TABLE 2 Saturated 1,4- Brine Dioxane Example Product Yield (%) anti:syn ee (%) Yield (%) anti:syn ee (%) 2-1

76 84:16 94 79 88:12 96 2-2

61 89:11 97 71 >95:5  99 2-3

67 91:9  98 71 88:12 98 2-4

72 >95:5  95 71 >95:5  94 2-5

68 >95:5  95 35 86:14 96 2-6

77 77:23 96 53 78:22 90 2-7

28 90:10 98 77 93:7  99 2-8

52 >95:5  97 69 >95:5  98 2-9

 9 >95:5  95 74 >95:5  98  2-10

88 72:28 92 87 78:22 99  2-11

quant. 78:22 92 88 78:22 98  2-12

65 71:29 84 quant. 77:23 98  2-13

73 74:26 96 86 77:23 98  2-14

84 72:28 86 84 76:24 99

Reference Example 2 Reduction Reaction

To a solution of N-((2R,3R)-2,4-dimethyl-1-oxopentan-3-yl)-p-toluenesulfonamide (30.0 mg, 0.1 mmol) in methanol (0.3 mL) was added sodium borohydride (37.8 mg, 1.0 mmol) at 0° C. The reaction mixture was stirred for 1 hr, and the reaction was quenched by addition of phosphoric acid buffer (pH 7). The reaction mixture was extracted with chloroform (3×10 mL), and the combined organic layer were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane:EtOAc=2:1) to give N-((2R,3R)-2,5-dimethyl-1-hydroxyhexan-3-yl)-p-toluenesulfonamide (yield, 95%).

¹H NMR (CDCl₃, 400 MHz): δ 0.66 (3H, d, J=6.8 Hz), 0.77 (3H, d, J=6.8 Hz), 0.87 (3H, d, J=7.2 Hz), 1.16-1.29 (2H, m), 1.30-1.43 (1H, m), 1.65-1.77 (2H, m), 1.80 (1H, br-s), 2.42 (3H, s), 3.38 (1H, tt, J=5.2, 8.0 Hz), 3.46 (1H, dd, J=5.2, 10.8 Hz), 3.77 (1H, dd, J=4.0, 11.2 Hz), 4.93 (1H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.76 (2H, d, J=8.0 Hz);

¹³C NMR (CDCl₃, 100 MHz): δ 13.6, 21.5, 21.9, 23.1, 24.3, 38.9, 42.2, 54.6, 64.6, 127.0, 129.5, 138.5, 143.1;

IR (neat): ν 3522, 3282, 2957, 1599, 1464, 1319, 1157, 1094, 1031, 815, 666, 553 cm⁻¹;

HRMS (ESI): [M+Na] calculated for ([C₁₅H₂₅NNaO₃S]): 322.1447. found 322.1453;

[α]_(D) ²¹° C. +21.1 (c 0.96, CHCl₃);

INDUSTRIAL APPLICABILITY

The production method of the present invention can provide a new method capable of producing an optically active β-aminoaldehyde compound from an imine compound. In the method, optically active β-aminoaldehyde compound (3) can be easily produced.

In addition, by using optically active pyrrolidine compound (4) having a particular structure, optically active β-aminoaldehyde compound (3) can be produced in good yield, superior enantioselectivity and diastereoselectivity (when R² in aldehyde compound (2) is not a hydrogen atom). 

The invention claimed is:
 1. A method of producing an optically active compound of formula (3):

wherein R¹ is a C₁-C₂₀ aliphatic hydrocarbon group optionally having substituent(s) selected from the following Group G1 or a hydrogen atom, R² is a C₁-C₂₀ hydrocarbon group optionally having substituent(s) selected from the following Group G1, a C₁-C₁₂ alkoxy group optionally having substituent(s) selected from the following Group G1, a C₁-C₁₂ alkylthio group optionally having substituent(s) selected from the following Group G1, a protected amino group, a heterocyclic group optionally having substituent(s) selected from the following Group G2, R^(X) is an amino-protecting group, and the carbon atom marked with ** is an asymmetric carbon atom, which comprises a step of reacting a compound of formula (1-1):

wherein R¹ and R^(X) are as defined above, or a compound of formula (1-2):

wherein R¹ and R^(X) are as defined above, and Ar^(X) is a phenyl group optionally having substituent(s) selected from the following Group G2, with a compound of formula (2): R²—CH₂CHO  (2) wherein R² is as defined above, in the presence of an optically active compound of formula (4):

wherein Ar¹ and Ar² are each independently a phenyl group optionally substituted by at least one C₁-C₁₂ fluorinated alkyl group, R⁵ is a hydrogen atom, a fluorine atom, a hydroxyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ fluorinated alkyloxy group or —OSiR⁶R⁷R⁸ wherein R⁶, R⁷ and R⁸ are each independently a C₁-C₈ alkyl group or a C₆-C₂₀ aryl group, and the carbon atom marked with * is an asymmetric carbon atom; <Group G1>: a group consisting of a C₆-C₂₀ aryl group optionally having substituent(s) selected from Group G2, an aromatic heterocyclic group optionally having substituent(s) selected from Group G2, a C₁-C₁₂ alkyl group, a C₁-C₁₂ alkoxy group, a C₁-C₁₂ alkyl group having C₆-C₂₀ aryl group(s) optionally having substituent(s) selected from Group G2, a C₁-C₁₂ alkoxy group having C₆-C₂₀ aryl group(s) optionally having substituent(s) selected from Group G2, a halogen atom, a C₂-C₁₃ alkylcarbonyl group, a C₂-C₁₃ alkoxycarbonyl group, a C₁-C₁₂ fluorinated alkyl group, a C₁-C₁₂ fluorinated alkyloxy group, a C₂-C₁₃ acyl group, a nitro group, a cyano group, a protected amino group and an oxo group <Group G2>: a group consisting of a C₁-C₁₂ alkyl group, a C₁-C₁₂ alkoxy group, a C₂-C₁₃ alkylcarbonyl group, a C₂-C₁₃ alkoxycarbonyl group, a C₁-C₁₂ fluorinated alkyl group, a C₁-C₁₂ fluorinated alkyloxy group, a C₂-C₁₃ acyl group, a nitro group, a cyano group, a protected amino group and a halogen atom.
 2. The method of claim 1, wherein the reaction is carried out in a solvent.
 3. The method of claim 2, wherein the solvent is water.
 4. The method of claim 2, wherein the solvent is water containing an inorganic salt.
 5. The method of claim 4, wherein the inorganic salt is sodium chloride.
 6. The method of claim 2, wherein the solvent is an ether solvent.
 7. The method of claim 1, wherein R⁵ is —OSiR⁶R⁷R⁸ wherein each symbol is as defined in claim 1, and Ar¹ and Ar² are each independently a phenyl group substituted with at least one C₁-C₁₂ fluorinated alkyl group.
 8. The method of claim 1, wherein Ar¹ and Ar² are each independently a phenyl group optionally substituted with at least one trifluoromethyl group.
 9. The method of claim 1, wherein Ar¹ and Ar² are each 3,5-bis(trifluoromethyl)phenyl. 